Neurosurgical apparatus and method

ABSTRACT

A method for delivering fluid to the brain of a subject using an intraparenchymal catheter, the method comprising the step of inserting the catheter 5 into the brain using a posterior to anterior approach and methods of treating neurodegenerative disorders using this delivery method, as well as methods for delivering fluid to an elongate structure of the brain using an intraparenchymal catheter, the method comprising the step of inserting a catheter into the brain along an insertion axis that is substantially aligned with a long axis of the elongate structure.

PRIOR RELATED APPLICATIONS

This is a continuation of application Ser. No. 16/454,637, filed Jun.27, 2019 which is a continuation of application Ser. No. 14/610,185,filed Jan. 30, 2015, now U.S. Pat. No. 10,369,329, issued Aug. 6, 2019,which claims the benefit of UK 1401552.3, filed Jan. 30, 2014, and UK1412941.5, filed Jul. 22, 2014. The disclosures of the prior applicationare hereby incorporated by reference herein in their entirety for allpurposes.

FIELD OF THE DISCLOSURE

This application is directed to an improved neurosurgical apparatus andmethod.

BACKGROUND OF THE DISCLOSURE

Relatively large lenticulo striate arteries penetrate the most ventralportion of the putamen and course through it from ventral to dorsal tosupply the basal ganglia and internal capsule. In passing through theputamen the calibre of the vessels reduces from ventral to dorsal and sodo the perivascular spaces. The perivascular spaces are in directcommunication with the extra cellular fluid in the putamen and arterialpulsations in the lenticulo striate vessels act in cooperation with theperi-vascular spaces to create fluid pumps that drive extra cellularfluid dorsoventrally in the opposite direction to the arterial supply.The extra cellular fluid is cleared into the perivascular spaces withincreasing efficiency as one moves from the dorsal to the ventralputamen as a consequence of the increasing calibre of the lenticulostriate vessels.

When delivering a drug by convection enhanced delivery into the putamenor other regions of the brain to treat conditions such as Parkinson'sdisease, Huntington's disease or other neurodegenerative disease, it isdesirable to fill the greater proportion of the target area with theinfused drug. It has been observed that poor volumetric distribution ofdrug infused, for example, into the putamen down a fine catheter whenthe tip of the catheter is in close proximity to large calibre lenticulostriate vessels in the ventral portion of the putamen. This is due to ahigher rate of clearance of extra cellular fluid and thus drug in theventral portion of the putamen than there is in its dorsal portion as aconsequence of the large calibre perivascular pumps.

Catheters or cannulae have previously been passed into regions of thebrain, such as the putamen, for the delivery of drugs (or transplantedcells) through a frontal burr hole at an angle of approximately 45° tothe anterior commissure—posterior commissure plane. The disadvantage ofthis trajectory is that, in order to place an adequate length of thecatheter or cannula within the putamen the frontal entry point in theskull needs to be very close to the mid sagittal plane because of theorientation of the putamen which angles laterally from its anterior toposterior aspect. The putamen also angles from medial to lateral in thevertical or coronal plane from its dorsal to ventral aspect. A frontalentry point close to the mid sagittal plane increases the risk ofcausing haemorrhage because the calibre and density of the veinsdraining the cortex into the sagittal sinus increase as they approachthe midline. The putamen is bean shaped with a concavity on its medialaspect and is tapered at its posterior end. A trajectory entering itsmost dorsal portion and passing at 45° into it will result in arelatively short catheter length contained within the putamen if thedistal end of the catheter is to remain within the structure. The shortlength of catheter that is within the structure limits the volume ofdrug that can be infused into the putamen as there is a tendency for thedrug to reflux along the length of the catheter, generally giving anelongate infusion volume. As described above, the clearance ofextracellular fluid and therefore of the infused drug will be greatestin the most ventral portion of putamen where the enlarged perivascularspaces act as fluid sumps. This will limit the distribution of the druginto the more dorsal aspects of the structure. An additionaldisadvantage of the above described trajectory is that the distal end ofthe catheter will be passing into a portion of the putamen which isdensely supplied by large calibre lenticulo striate vessels andtherefore the risk of haemorrhage is increased.

Particular problems associated with delivering infusate to the putamenof rhesus and cynomolgous monkeys were described in Brady et al. 2013,which measured the loss of volume due to overflow, perivascular flow,backflow and catheter tract leakage. Brady carried out infusions usingcatheters inserted from a superior position, which is the commonlyaccepted approach to target structures in the brain (as described inSlevin et al. 2005). However, Brady notes that an axial cathetertrajectory passing through the frontal sinuses, although not commonlyused due to technical difficulties in implanting catheters through thisstructure and the risk of infection when traversing the mucosa linedsinus, may have a geometric advantage due to the catheter being insertedalong the long axis of the putamen.

In view of the problems associated with delivering fluid to the brainthere is a need to provide improved methods for this delivery.

SUMMARY OF THE DISCLOSURE

In a first embodiment, there is provided a method for delivering a fluidto a brain of a subject. The method may include delivering the fluid tothe brain by inserting at least one intraparenchymal catheter into atarget area of the brain using a posterior to anterior approach.

In another embodiment, there is provided a method for treating aneurodegenerative disorder. The method may include delivering a fluid toa brain of a subject by inserting at least one intraparenchymal catheterinto a target area of the brain using a posterior to anterior approach.

In another embodiment, there is provided a method for delivering a fluidto an elongate structure of a brain of a subject. The method may includedelivering the fluid to the elongate structure by inserting at least oneintraparenchymal catheter into the brain along an insertion axis that issubstantially aligned with a long axis of the elongate structure.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1 to 3 illustrate prior techniques that involve insertingcatheters through a frontal burr hole at an angle of approximately 45°to the anterior commissure—posterior commissure plane.

FIGS. 4 to 6 shows catheter placement in accordance with an embodiment.The catheter can thus be seen to extend substantially along the longaxis of the putamen. Fluid thus refluxes back from the catheter tip tothe step in the outer surface profile of the catheter, thereby providinga distribution that covers a large part of the putamen.

FIG. 7 shows how a percutaneous port based system may be used to providea fluid connection to catheters placed in accordance an embodiment.

FIGS. 8 and 9 show an anterior to posterior trajectory for catheterdelivery to the putamen and FIGS. 10 to 13 illustrate delivery achievedusing an anterior to posterior trajectory.

FIG. 14 shows the effect of trajectory on distribution volumes in theputamen as observed following 400 μl infusion volumes in human putamen(95% CI for the Mean).

FIG. 15 shows the effect of trajectory on percentage coverage of Putamen(per catheter) and illustrates the percentage coverage observed directlyrelative to the size of each putamen into which the catheter wasimplanted. Data have not been normalised to account for differences inthe volumes of each Putamen (95% CI for the Mean).

FIG. 16 shows the effect of trajectory on percentage coverage of putamen(per pair of catheters)—as in FIG. 15 but coverage following pairs ofcatheters are displayed (95% CI for the Mean).

FIG. 17 shows a schematic view of the human brain.

FIG. 18 shows a schematic coronal view of the human brain.

FIG. 19 shows a schematic perspective view of the basal ganglia of thehuman brain.

FIG. 20 shows another schematic sagittal view of the human brain.

DETAILED DESCRIPTION

In disclosed embodiments, the fluid may be delivered to structureswithin the brain, including one or more of the hippocampus, the putamen,the globus pallidus, the amygdala, the nucleus basalis, the nucleusaccumbens, the substantia nigra, the caudate nucleus and the subthalamicnucleus, as shown in FIGS. 18, 19 and 20. The target structurespreferably have a long axis orientated in an anterior to posteriordirection. This particular orientation allows the structures to betargeted along their length, allowing a greater length of catheter to beinserted into the structure, which can reduce catheter reflux.Accordingly, more fluid can be delivered into the structure.

In a preferred embodiment, the catheter is inserted along a trajectorythrough the occipitoparietal region, approximately parallel to theanterior commissure—posterior commissure plane, as shown in FIG. 17.

The posterior to anterior approach allows the disclosed method to becarried out on a subject such as a patient under general anaesthetic andin a prone position. Movement of the brain during neurosurgery can be aparticular problem as even a few millimetres of displacement cansignificantly affect the accuracy of e.g. a catheter inserted into thebrain. Not only will the brain move if and when the patient is moved,but the action of inserting a catheter can itself displace the brain inthe direction of the insertion. Indeed, the present inventors haveidentified that during a conventional superior/vertical approach intothe brain the brain can displace in potentially two differentdirections, making it difficult for surgeons to finely control catheterplacement. However, the prone position of the patient in disclosedmethods can have advantages, as when the patient is turned from theirback onto their front the brain displaces anteriorly in the skull. Thecatheter insertion is then from the posterior toward the anterior,however, as the brain has already displaced anteriorly any furtherdisplacement due to catheter insertion is likely to be minimal. Thedisclosed methods can therefore provide highly accurate targeting ofstructures in the brain. In preferred embodiments, the patient may be ahuman.

The insertion trajectory may be substantially aligned with the long axisof a target structure, such as the hippocampus, the putamen, the globuspallidus, the amygdala, the nucleus basalis, the nucleus accumbens, thesubstantia nigra, the caudate nucleus and the subthalamic nucleus. Inorder to improve the distribution of an infused drug delivered by CEDinto a target structure, in embodiments, the method comprises using acatheter insertion trajectory that passes from posterior to anteriorthrough the occipital, occipitoparietal, or occipitotemporal regionapproximately parallel to the anterior commissure—posterior commissureplane. When targeting the long axis of the putamen (which may includethe head of the caudate nucleus along the same trajectory), the globuspallidus, the nucleus basalis, the nucleus accumbens, the amygdala, thesubstantia nigra, the subthalamic nucleus, or the hippocampus, thistrajectory preferably passes through the optic radiation, lateral to theposterior horn of the lateral ventricle and thence into the posteriorpart of the structure and along its long axis to its anterior portion.

The fluid may be delivered into structures of the brain that are atleast 2 cm or at least 4 cm or at least 6 cm from the skull of thepatient. The structures may be in areas of the forebrain and/or in areasof the midbrain.

In another embodiment, the method may include delivering a fluid (e.g. afluid containing a therapeutic agent) to the brain. The fluid deliveryis conveniently by convection enhanced delivery (CED). The methodpreferably comprises the step of inserting a catheter into the brainalong a trajectory through the occipitoparietal region approximatelyparallel (e.g. parallel to within 10°, 20°, 30°, or 40°) to the anteriorcommissure—posterior commissure plane. The trajectory preferably passesfrom posterior to anterior.

In another embodiment, the method may include delivering a fluid to atarget structure such as the hippocampus, the putamen, the globuspallidus, the amygdala, the nucleus basalis, the nucleus accumbens, thesubstantia nigra, the caudate nucleus and the subthalamic nucleus thatcomprises the step of inserting a catheter into the brain along an axisthat is substantially aligned (e.g. to within 10°, 20°, 30° or 40°) withthe long axis of the structure. The insertion trajectory preferablypasses from posterior to anterior.

An advantage of disclosed embodiments is that the inserted catheter willhave a greater portion confined to the target structure, typically about10 to about 40 min or about 15 to about 30 mm, whereas a more verticaltrajectory through the frontal region could achieve a catheter length ofbetween 10 and 15 min most typically. Indeed, the upper limit for thelength of the catheter confined to the target structure using methods ofdisclosed embodiments is limited only by the size of the targetstructure in the patient.

Importantly, the catheter placed along the long axis of the putamenwould avoid the larger calibre and greater density of lenticulo striatevessels, reducing the likelihood of causing haemorrhage and reducing theimpact of perivascular pumping of fluid from the extracellular spacewhich is greater as one moves from the dorsal to the ventral striatum.This also has the advantage of potentially increasing the volume ofdistribution in the target structure and as drug would be drawnventrally by the flow of extracellular fluid which occurs predominantlyin a dorsoventral direction, this would achieve greater total coverageof the structure than would be achieved by the more conventionaltrajectory. Passing the catheter tip along this trajectory into the headof the caudate nucleus would be advantageous for treating Huntingdon's,multiple system atrophy and cortico-basal degeneration.

Optimising the volume of distribution of therapy within regions of thebrain, such as the hippocampus, the putamen, the globus pallidus, theamygdala, the nucleus basalis, the nucleus accumbens, the substantianigra, the caudate nucleus and the subthalamic nucleus, and avoidinginadvertent clearance along the perivascular spaces is particularlyimportant when delivering viral vectors for gene therapy. This isbecause uncontrolled transfection of neurons at distant sites within theCNS could cause long-term and debilitating side effects.

The method may be used to deliver any therapeutic agent. The method maybe used to treat conditions such as Parkinson's disease, Huntington'sdisease, Alzheimer's disease, Multiple-System Atrophy, ProgressiveSupranuclear Palsy (PSP), dystonia, tremor, Tourette's syndrome or otherneurodegenerative diseases.

The therapeutic agent may be selected from, for example, one or more ofa chemotherapy drug, a neurotrophin, an enzyme, a growth factor, anantibody, an immunotoxin, small inhibitory RNA (siRNA), antisenseoligonucleotides, viral vectors, drug releasing nanoparticles (includingliposomes and micels), transgenes and combinations or mixtures thereof.In embodiments, the therapeutic agent may be glial cell-derivedneurotrophic factor (GDNF) or neprilysin, which may be administeredalone or in combination or consecutively. The combination and/orconsecutive administration of GDNF and neprilysin may be used for thetreatment of Alzheimer's disease.

The therapeutic agent may be administered in combination with artificialcerebrospinal fluid (aCSF). ACSF as disclosed herein may compriseglucose, proteins and ionic constituents. Alternatively, the aCSF mayomit glucose, so as to reduce the likelihood of bacterial growth in anycatheter used to administer the composition to a subject. Mostpreferably, the aCSF does not comprise glucose or proteins.

In another embodiment, the method may include treating aneurodegenerative disorder, the method comprising delivering fluid tothe brain of a patient using an intraparenchymal catheter, wherein thecatheter is inserted into the brain using a posterior to anteriorapproach as described above.

In a further aspect, the method may include delivering fluid to anelongate structure of the brain using an intraparenchymal catheter, themethod comprising the step of inserting a catheter into the brain alongan insertion axis that is substantially aligned with a long axis of theelongate structure. Suitable elongate structures include thehippocampus, the putamen, the globus pallidus, the amygdala, the nucleusbasalis, the nucleus accumbens, the substantia nigra, the caudatenucleus or the subthalamic nucleus.

Disclosed embodiments may use a catheter of the type described inWO03/077785 (incorporated herein by reference) that is inserted via aguide tube. A recessed step catheter as described in WO2014/016591(incorporated herein by reference) may also be used. Advantageously, acatheter and/or cannula having a stepped outer profile may be employed.Any step or steps in the outer profile are preferably located within thestructure of the putamen. In addition to the surgical methods outlinedabove, embodiments extend to a catheter adapted for insertion inaccordance with the method described above. The method may involveimplanting a percutaneous port based catheter system, for example asdescribed in WO2008/062173 or WO2011/098769 (both incorporated herein byreference).

The fluid may be administered via at least one convection enhanceddelivery (CED) catheter, especially an intraparenchymal catheter.Alternatively, the fluid may be administered via at least two, at leastthree or four or more such catheters. For example, two catheters may beused to administer the fluid bilaterally.

The fluid may be delivered via at least one or at least two chronicallyimplanted CED catheters or via three or more of such catheters.Chronically implanted CED catheters refer to catheters that will be leftin situ in the brain of a subject for at least 30 days, optionally forat least six months. Chronically implanted catheters may remain in placefor up to one year or even for the lifetime of a subject.

The fluid may be administered on at least two, preferably three,optionally four consecutive days. Alternatively, the fluid may beadministered on two out of three, four or five days, or three out offour, five, six or seven days.

Whether or not the fluid is for administration for a number ofconsecutive days or for regular administration over a number of days, itmay independently or additionally be for administration weekly,fortnightly, monthly, every six, eight, twelve or fifteen or more weeks.For example, a cycle of two or three days of infusions may be repeatedevery fortnight. Alternatively, it may be for administration in a seriesof cycles of infusions, with 6, 7, 8, 9, 10, 11 or 12 days between theend of a first cycle of infusions and the next cycle of infusions.

For example, the fluid may be for administration by infusion for between6 and 10, especially between 7 and 9 hours, each day for threeconsecutive days. This pattern of administration may then be repeatedweekly, or fortnightly, or for example with 6, 7, 8, 9, 10, 11 or 12days between the end of a first cycle of three days of infusions and thenext three days of infusions.

EXAMPLES

Artificial cerebrospinal fluid with an MRI visible tracer (Gadolinium)was infused into the human putamen through intra-cerebrally placed neurocatheters as described in WO 2014/016591. The surgery utilised arobot-guided stereotactic CED system as described in Banta et al 2013 tocompare the volume of distribution following (i) a conventional verticalapproach into the putamen with (ii) an anterior to posterior insertiontrajectory and (iii) a posterior to anterior insertion trajectory.

Both the anterior to posterior and posterior to anterior trajectoriespassed approximately parallel to the anterior commissure—posteriorcommissure plane to target the long axis of the putamen. The entry pointfor the anterior to posterior trajectory was located between the orbitsand the coronal suture, while the posterior to anterior trajectory hadan entry point in the occipitoparietal region and passed through theoptic radiation, lateral to the posterior horn of the lateral ventricle.

Quantification of the infusion distribution was made possible throughthe use of Renishaw's Neuro|Inspire™ (Renishaw Plc., Gloucestershire,UK) surgical planning software with an in-house software module.Clinical guidance was given to define the boundaries of the infusionsand profiles were manually drawn around the visible infusion on each MRIslice. The software module then reconstructs the profiles into a 3Dvolume, multiplying the areas by the slice thickness.

The distribution volume was identified manually by assigning voxels ofMRI scans to each catheter via a visual assessment and the results areshown in FIG. 14.

Percentages of coverage were calculated by dividing the volume ofdistribution by the volume of the putamen into which the infusion wastargeted and are shown in FIG. 15.

Percentage coverage for pairs of catheters were assigned where twocatheters infused into a single putamen, total distribution within thestructure was then divided by the volume of the putamen and results areshown in FIG. 16.

As can be seen in the results, both the anterior to posterior andposterior to anterior approaches improved the volume of distributionover that achieved using the conventional vertical approach. However,surprisingly, while both the anterior to posterior and posterior toanterior approaches targeted the long axis of the putamen, the volume ofdistribution was significantly improved in the posterior to anteriorapproach. Without being bound by theory, the inventor believes that theangle of insertion needed to avoid the eye of a patient in an anteriorto posterior approach leads to the reduced volume of distribution. Aposterior to anterior approach allows the angle of insertion to beoptimised, which improves the volume of distribution. This approach alsohas cosmetic benefits for patients as the catheter ports can usually behidden under the patient's hair on the back of their head.

It will be appreciated that the above-disclosed features and functions,or alternatives thereof, may be desirably combined into differentsystems or methods. Also, various alternatives, modifications,variations or improvements may be subsequently made by those skilled inthe art, and are also intended to be encompassed by the followingclaims. As such, various changes may be made without departing from thespirit and scope of this disclosure as defined in the claims.

REFERENCES

-   Barua N U, Lowis S P, Woolley M, O Sullivan S, Harrison R, Gill S S.    Acta Neurochir (Wein). 2013 155:1459-65-   Brady M L, Raghavan R, Alexander A, Kubota K, Sillay K and Emborg    M E. Stereotact Funct Neurosurg 2013 91:69-78-   Slevin J T, Herhardt G A, Smith C D, Gash D M, Kryscio R and    Young B. J. Neurosurg. 2005 102:216-222

What is claimed is:
 1. A method for intraparenchymal delivery of a fluidto an elongate structure of a brain of a subject, the method comprisingdelivering the fluid to the elongate structure by inserting at least oneintraparenchymal catheter having at least one step into the brain usinga posterior to anterior approach along an insertion axis that issubstantially aligned with a long axis of the elongate structure.
 2. Themethod of claim 1, wherein the at least one step is located within theelongate structure.
 3. The method of claim 1, wherein the insertion axisis aligned with the long axis of the elongate structure to within 40° orless.
 4. The method of claim 1, wherein the catheter is inserted into aposterior portion of the elongate structure along the long axis to ananterior portion of the elongate structure.
 5. The method of claim 1,wherein the subject is under general anesthetic and in a prone position.6. The method of claim 1, wherein the fluid includes at least onetherapeutic agent selected from the group consisting of a chemotherapydrug, a neurotrophin, an enzyme, a growth factor, an antibody, animmunotoxin, small inhibitory RNA (siRNA), antisense oligonucleotides,viral vectors, drug releasing nanoparticles, and transgenes.
 7. A methodfor treating a neurodegenerative disorder, the method comprisingdelivering a fluid to the brain by inserting at least oneintraparenchymal catheter having at least one step into a target volumeof the brain using a posterior to anterior approach along an insertionaxis that is substantially aligned with a long axis of the targetvolume.
 8. The method of claim 7, wherein the step is located within thetarget volume.
 9. The method of claim 7, wherein the insertion axis isaligned with the long axis of the target volume to within 40° or less.10. The method of claim 7, wherein the catheter is inserted into aposterior portion of the target volume along the long axis to ananterior portion of the target volume.
 11. The method of claim 7,wherein the subject is under general anesthetic and in a prone position.12. The method of claim 7, wherein the target volume is an elongatestructure of the brain.
 13. The method of claim 7, wherein theneurodegenerative disorder is at least one of Multiple-System Atrophy,Progressive Supranuclear Palsy (PSP), Parkinson's Disease, Huntington'sDisease, dystonia, tremor, Tourette's syndrome and lysosomal storagediseases.
 14. The method of claim 7, wherein the fluid includes at leastone therapeutic agent selected from the group consisting of achemotherapy drug, a neurotrophin, an enzyme, a growth factor, anantibody, an immunotoxin, small inhibitory RNA (siRNA), antisenseoligonucleotides, viral vectors, drug releasing nanoparticles, andtransgenes.
 15. A method for treating Huntington's disease, the methodcomprising delivering a fluid comprising a transgene to the brain byinserting at least one catheter having at least one step into anelongate structure of the brain using a posterior to anterior approachalong an insertion axis that is substantially aligned with a long axisof the elongate structure, wherein the elongate structure is selectedfrom the head of caudate nucleus and the putamen and wherein the step islocated within the elongate structure.
 16. The method of claim 15,wherein the at least one step is located within the elongate structure.17. The method of claim 15, wherein the catheter is an intraparenchymalcatheter.
 18. The method of claim 15, wherein the insertion axis isaligned with the long axis of the target volume to within 40° or less.